Skip to main content

Advertisement

SpringerLink
Log in

Persistent IL-10 production is required for glioma growth suppressive activity by Th1-directed effector cells after stimulation with tumor lysate-loaded dendritic cells

  • Lab investigation-human/animal tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Injection of dendritic cells (DC) pulsed with tumor antigens is a novel treatment strategy against malignancies, and aims to elicit anti-tumoral cell-mediated immune responses. We studied the in vitro proliferative responses and cytokine production in T cell cultures after 2 stimulations with autologous DC loaded with tumor lysates derived from glioblastoma multiforme (GBM) cells in the presence of recombinant interleukin (rIL)−6/rIL-12 in the first, and rIL-2/rIL-7 in the second stimulation. After the second stimulation, T cells were co-cultured with glioblastoma (GBM) cells and tumor growth suppression by T cells was assessed using a MTT assay. Although loaded DC induced a significant shift towards T helper cell type 1 (Th1) cytokine production as compared to unloaded DC, persistent interleukin (IL)-10 production by T cells both at the end of 2 stimulations with loaded DC and during the effector phase was also required for their tumor suppressive activity. A stronger glioma growth suppressive activity by T cells stimulated with tumor lysate-loaded DC than by control T cells, cultured with unloaded DC, was seen only if the relative IL-10 production after two stimulations with loaded DC was at least 40% of the IL-10 production after two stimulations with unloaded DC. If less than 40% IL-10 was produced in the experimental condition compared to the control condition, T cells also lost their tumor growth suppressive activity. Addition of rIL-10 during stimulation increased the suppressive activity on tumor cell viability and interferon (IFN)-γ production by T cells that showed Th1 response upon stimulation with loaded DC. The data point towards the production of both IFN-γ and IL-10 by responding effector T cells, and towards an immune modulatory rather than immune suppressive role of IL-10 to generate anti-tumoral effector T cells against GBM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Fleury A, Menegoz F, Grosclaude P, Daures JP, Henry Amar M, Raverdy N, Schaffer P, Poisson M, Delattre JY (1997) Descriptive epidemiology of cerebral gliomas in France. Cancer 79:1195–1202

    Article  PubMed  CAS  Google Scholar 

  2. Tamber MS, Rutka JT (2003) Pediatric supratentorial high-grade gliomas. Neurosurg Focus 14: http://www.medscape.com/viewarticle/449870

  3. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoom MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer EA, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Eng J Med 352:987–996

    Article  CAS  Google Scholar 

  4. Kleihues P, Soylemezoglu F, Schauble B, Scheithauer BW, Burger PC (1995) Histopathology, classification, and grading of gliomas. Glia 15:211–221

    Article  PubMed  CAS  Google Scholar 

  5. Siesjo P, Visse E, Sjogren HO (1996) Cure of established, intracerebral rat gliomas induced by therapeutic immunizations with tumor cells and purified APC or adjuvant IFN-gamma treatment. J Immunother Emphasis Tumor Immunol 19:334–345

    PubMed  CAS  Google Scholar 

  6. Liau LM, Black KL, Prins RM, Sykes SN, DiPatre PL, Cloughesy TF, Becker DP, Bronstein JM (1999) Treatment of intracranial gliomas with bone marrow-derived dendritic cells pulsed with tumor antigens. J Neurosurg 90:1115–1124

    PubMed  CAS  Google Scholar 

  7. Heimberger AB, Crotty LE, Archer GE, McLendon RE, Friedman A, Dranoff G, Bigner DD, Sampson JH (2000) Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma. J Neuroimmunol 103:16–25

    Article  PubMed  CAS  Google Scholar 

  8. Insug O, Ku G, Ertl HC, Blaszczyk-Thurin M (2002) A dendritic cell vaccine induces protective immunity to intracranial growth of glioma. Anticancer Res 22:613–621

    PubMed  CAS  Google Scholar 

  9. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ (2004) Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 64:4973–4979

    Article  PubMed  CAS  Google Scholar 

  10. De Vleeschouwer S, Van Calenbergh F, Demaerel P, Flamen P, Rutkowski S, Kaempgen E, Wolff JEA, Plets C, Sciot R, Van Gool SW (2004) Transient local response and persistent tumor control of recurrent malignant glioma treated with combination therapy including dendritic cell therapy. J Neurosurg Spine 100:492–497

    Google Scholar 

  11. Rutkowski S, De Vleeschouwer S, Kaempgen E, Wolff JEA, Kuhl J, Demaerel P, Warmuth-Metz M, Flamen P, Van Calenbergh F, Plets C, Sorensen N, Opitz A, Van Gool SW (2004) Surgery and adjuvant dendritic cell-based tumour vaccination for patients with relapsed malignant glioma, a feasibility study. Br J Cancer 91:1656–1662

    PubMed  CAS  Google Scholar 

  12. Yamanaka R, Abe T, Yajima N, Tsuchiya N, Homma J, Kobayashi T, Narita M, Takahashi M, Tanaka R (2003) Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial. Br J Cancer 89:1172–1179

    Article  PubMed  CAS  Google Scholar 

  13. De Vleeschouwer S, Arredouani M, Ade M, Cadot P, Vermassen E, Ceuppens JL, Van Gool SW (2005) Uptake and presentation of malignant glioma tumor cell lysates by monocyte-derived dendritic cells. Cancer Immunol Immunother 54:372–382

    Article  PubMed  Google Scholar 

  14. Romani N, Reider D, Heuer M, Ebner S, Kämpgen E, Eibl B, Niederwieser D, Schuler G (1996) Generation of mature dendritic cells from human blood. An improved method with special regard to clinical applicability. J Immunol Methods 196:137–151

    Article  PubMed  CAS  Google Scholar 

  15. Schuler-Thurner B, Schultz ES, Berger TG, Weinlich G, Ebner S, Woerl P, Bender A, Feuerstein B, Fritsch PO, Romani N, Schuler G (2002) Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J Exp Med 195:1279–1288

    Article  PubMed  CAS  Google Scholar 

  16. Bullens DMA, Rafiq K, Charitidou L, Peng X, Kasran A, Warmerdam PAM, Van Gool SW, Ceuppens JL (2001) Effects of costimulation by CD58 on human T cell cytokine production: a selective cyokine pattern with induction of high IL-10 production. Int Immunol 13:181–191

    Article  PubMed  CAS  Google Scholar 

  17. Chaux P, Vantomme V, Coulie P, Boon T, vanderBruggen P (1998) Estimation of the frequencies of anti-MAGE-3 cytolytic T-lymphocyte precursors in blood from individuals without cancer. Int J Cancer 77:538–542

    Article  PubMed  CAS  Google Scholar 

  18. Herr W, Ranieri E, Olson W, Zarour H, Gesualdo L, Storkus WJ (2000) Mature dendritic cells pulsed with freeze-thaw cell lysates define an effective in vitro vaccine designed to elicit EBV-specific CD4(+) and CD(8) T lymphocyte response. Blood 96:1857–1864

    PubMed  CAS  Google Scholar 

  19. van der Bruggen P, Bastin J, Gajewski TF, Coulie PG, Boel P, De Smet C, Traversari C, Townsend A, Boon T (1994) A peptide encoded by human gene MAGE-3 and presented by HLA-A2 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE-3. Eur J Immunol 24:3038–3043

    Article  PubMed  Google Scholar 

  20. Knüpfer MM, Knüpfer H, Jendrossek V, Van Gool SW, Wolff JEA, Keller E (2001) Interferon-gamma inhibits growth and migration of A172 human glioblastoma cells. Anticancer Res 21:3989–3994

    PubMed  Google Scholar 

  21. Matthews JN, Altman DG, Campbell MJ, Royston P (1990) Analysis of serial measurements in medical research. Bmj 300:230–235

    Article  PubMed  CAS  Google Scholar 

  22. Moudgil A, Toyoda M, Galfayan K, Jordan SC (1997) Selective expression of the interleukin-2 gene discriminates between the auto- and allo-mixed lymphocyte reaction. Transpl Immunol 5:35–38

    Article  PubMed  CAS  Google Scholar 

  23. Dong C, Flavell RA (2001) Th1 and Th2 cells. Curr Opin Hematol 8:47–51

    Article  PubMed  CAS  Google Scholar 

  24. Schuler T, Kammertoens T, Preiss S, Debs P, Noben-Trauth N, Blankenstein T (2001) Generation of tumor-associated cytotoxic T lymphocytes requires interleukin 4 from CD8(+) T cells. J Exp Med 194:1767–1775

    Article  PubMed  CAS  Google Scholar 

  25. Segal BM, Glass DD, Shevach EM (2002) Cutting Edge: IL-10-producing CD4 +  T cells mediate tumor rejection. J Immunol 168:1–4

    PubMed  CAS  Google Scholar 

  26. Carter LL, Dutton RW (1996) Type 1 and type 2: a fundamental dichotomy for all T-cell subsets. Curr Opin Immunol 8:336–342

    Article  PubMed  CAS  Google Scholar 

  27. Dobrzanski MJ, Reome JB, Hollenbaugh JA, Dutton RW (2004) Tc1 and tc2 effector cell therapy elicit long-term tumor immunity by contrasting mechanisms that result in complementary endogenous type 1 antitumor responses. J Immunol 172:1380–1390

    PubMed  CAS  Google Scholar 

  28. Zinberg M, Francus T, Weksler ME, Siskind GW, Karpatkin S (1982) Abnormal autologous mixed lymphocyte reaction in autoimmune thrombocytopenic purpura. Blood 59:148–151

    PubMed  CAS  Google Scholar 

  29. Rafiq K, Charitidou L, Bullens DMA, Kasran A, Lorré K, Ceuppens JL, Van Gool SW (2000) Regulation of IL-10 production by human T cells. Scand J Immunol

  30. Koch F, Stanzl U, Jennewein P, Janke K, Heufler C, Kämpgen E, Romani N, Schuler G (1996) High level IL-12 production by murine dendritic cells: Upregulation via MHC class II and CD40 molecules and downregulation by IL-4 and IL-10. J Exp Med 184:741–746

    Article  PubMed  CAS  Google Scholar 

  31. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765

    Article  PubMed  CAS  Google Scholar 

  32. Akdis CA, Blaser K (2001) Mechanisms of interleukin-10-mediated immune suppression. Immunology 103:131–136

    Article  PubMed  CAS  Google Scholar 

  33. Hagenbaugh A, Sharma S, Dubinett SM, Wei SH, Aranda R, Cheroutre H, Fowell DJ, Binder S, Tsao B, Locksley RM, Moore KW, Kronenberg M (1997) Altered immune responses in interleukin 10 transgenic mice. J Exp Med 185:2101–2110

    Article  PubMed  CAS  Google Scholar 

  34. Halak BK, Maguire HC Jr, Lattime EC (1999) Tumor-induced interleukin-10 inhibits type 1 immune responses directed at a tumor antigen as well as a non-tumor antigen present at the tumor site. Cancer Res 59:911–917

    PubMed  CAS  Google Scholar 

  35. Kim BG, Joo HG, Chung IS, Chung HY, Woo HJ, Yun YS (2000) Inhibition of interleukin-10 (IL-10) production from MOPC 315 tumor cells by IL-10 antisense oligodeoxynucleotides enhances cell-mediated immune responses. Cancer Immunol Immunother 49:433–440

    Article  PubMed  CAS  Google Scholar 

  36. Nitta T, Hishii M, Sato K, Okumura K (1994) Selective expression of interleukin-10 gene within glioblastoma multiforme. Brain Res 649:122–128

    Article  PubMed  CAS  Google Scholar 

  37. Berman RM, Suzuki T, Tahara H, Robbins PD, Narula SK, Lotze MT (1996) Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J Immunol 157:231–238

    PubMed  CAS  Google Scholar 

  38. Zheng LM, Ojcius DM, Garaud F, Roth C, Maxwell E, Li Z, Rong H, Chen J, Wang XY, Catino JJ, King I (1996) Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism. J Exp Med 184:579–584

    Article  PubMed  CAS  Google Scholar 

  39. Groux H, Cottrez F, Rouleau M, Mauze S, Antonenko S, Hurst S, McNeil T, Bigler M, Roncarolo MG, Coffman RL (1999) A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells. J Immunol 162:1723–1729

    PubMed  CAS  Google Scholar 

  40. Book AA, Fielding KE, Kundu N, Wilson MA, Fulton AM, Laterra J (1998) IL-10 gene transfer to intracranial 9L glioma: tumor inhibition and cooperation with IL-2. J Neuroimmunol 92:50–59

    Article  PubMed  CAS  Google Scholar 

  41. Terness P, Bauer TM, Rose L, Dufter C, Watzlik A, Simon H, Opelz G (2002) Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196:447–457

    Article  PubMed  CAS  Google Scholar 

  42. Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A, Candeloro P, Belladonna ML, Bianchi R, Fioretti MC, Puccetti P (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3:1097–1101

    Article  PubMed  CAS  Google Scholar 

  43. MacKenzie CR, Gonzalez RG, Kniep E, Roch S, Daubener W (1999) Cytokine mediated regulation of interferon-gamma-induced IDO activation. Adv Exp Med Biol 467:533–539

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This project is supported by the Olivia Hendrickx Research Fund, The Belgian Federation against Cancer, Electrabel Netmanagement Vlaanderen, and charities from private families.

Author information

Authors and Affiliations

  1. Laboratory of Experimental Immunology, Catholic University Leuven, Herestraat 49, Belgium, Leuven, 3000, Europe

    Steven De Vleeschouwer, Isabel Spencer Lopes, Jan L. Ceuppens & Stefaan W. Van Gool

  2. Department of Neurosurgery, University Hospital Gasthuisberg, Belgium, Leuven, Europe

    Steven De Vleeschouwer

  3. Department of Pediatric Hemato-oncology, University Hospital Gasthuisberg, Belgium, Leuven, Europe

    Stefaan W. Van Gool

Authors
  1. Steven De Vleeschouwer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isabel Spencer Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jan L. Ceuppens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefaan W. Van Gool
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven De Vleeschouwer.

Additional information

SDV and ISL were recipients of a grant from the Emmanuel van der Schueren Fund.

SWVG is Senior Clinical Investigator of the Fund for Scientific Research—Flanders (Belgium) (F.W.O.-Vlaanderen)

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Vleeschouwer, S., Spencer Lopes, I., Ceuppens, J.L. et al. Persistent IL-10 production is required for glioma growth suppressive activity by Th1-directed effector cells after stimulation with tumor lysate-loaded dendritic cells. J Neurooncol 84, 131–140 (2007). https://doi.org/10.1007/s11060-007-9362-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-007-9362-y

Keywords

Search

Navigation